Recent studies of the frequency-dependent block of excitability in nerve by local anesthetics have established a new understanding of how these agents work at the molecular level. Since those new findings may relate to the antiarrhythmic effectiveness of local anesthetics in the heart, I am undertaking extensive new investigations and tests of these recently developed concepts in cardiac muscle. Many different local anesthetics, as well as several types of antiarrhythmics from other drug classes, will be tested for frequency-dependent enhancements of myocardial excitability block (measured as decrements in maximum rate of depolarization of intracellularly recorded action potentials). Recovery from this use-dependent increase in exciability block will also be studied in detail, especially regarding the effects of membrane potential and drug dose on this recovery process. Experimental preparation:guinea pig papillary muscle.